Male Sprague-Dawley rats were treated with clofibrate (CLOF) in the diet for 2 years or with 4 i.p. injections of either diethylnitrosamine (DEN) or benzidine (BZ) followed by phenobarbital (PB) in the diet for 67 weeks, or just with PB for 41 weeks. Animals were killed at frequent intervals, some while still on treatment and others after 3 or 6 months withdrawal of treatment. The livers were subjected to cytochemical measurements of the parenchyma, foci, nodules and carcinomas. The parenchyma of the CLOF groups showed, in general, increases in glucose-6-phosphate dehydrogenase (G-6PD), alpha-glycerophosphate dehydrogenase (alpha-GPD), 5'-nucleotidase (5'-Nu), acid phosphatase (AP) and catalase and decreases in uricase and glutathione (GSH). CLOF induced a low incidence of GSH positive foci; nodules showed universally lower levels of catalase and GSH. In the DEN/PB and BZ/PB groups the parenchyma showed increases (even before PB treatment started) in G-6PD and in gamma-glutamyl transpeptidase (gamma-GT) and decreases in GSH. DEN raised and BZ lowered 5'-Nu. Neither initiator affected alpha-GPD. Both initiators caused a high incidence of foci positive for G-6PD and for gamma-GT; nodules induced by DEN/PB were mainly positive for gamma-GT and showed an erratic response to the other parameters. Carcinomas, found only after DEN/PB, were all positive for G-6PD and, with one exception, all were negative for alpha-GPD, 5'-Nu, AP and GSH. All changes regressed within 3 months of withdrawal of CLOF but not after withdrawal of PB from DEN-initiated animals. In conclusion G-6PD, alpha-GPD and 5'-Nu may be useful histocytochemical parameters for studying the precarcinogenic hepatic changes and nodules induced by peroxisome proliferators and by genotoxic hepatocarcinogens.